PROJECT ABSTRACT There is increasing recognition that the management of post-surgical and post-trauma sepsis is improving, and the incidence of both multiple organ failure (MOF) and in-hospital mortality are decreasing. Although these trends are generally favorable, there is a dark side to the reduced in-hospital mortality. Associated with this is the appearance of a new phenotype of chronically, critically ill (CCI) patients that we have termed PICS (persistent inflammation/immunosuppression and catabolism syndrome). This project seeks to identify the underlying mechanism(s) that result in the development of PICS. Our overarching hypothesis is that sepsis drives the expansion of myeloid-derived suppressor cells (MDSCs) (Specific Aim #1), and it is the activity of these suppressor cells which contributes to the development of PICS in patients with CCI (Specific Aims #2,3). We have three specific aims: Specific Aim #1: to determine whether CCI is associated with the early and sustained expansion of MDSC populations (>15% of total leukocyte population) in sepsis patients. We anticipate that patients with sepsis who have an uncomplicated hospital course will have an early rise in the numbers of MDSCs, but these will resolve rapidly with time. In contrast, patients who develop CCI will experience a sustained and heightened rise in MDSCs with both an increased suppressor and inflammatory phenotypes. Specific Aim #2: to determine whether the persistent expansion of MDSCs is an essential requirement for morbid outcomes and an ongoing inflammatory, immunosuppressive and catabolic response (PICS) in CCI patients. We hypothesize that the persistent expansion of MDSCs is an essential requirement for morbid outcomes and the development of PICS in patients with CCI. MDSC expansion and a detailed analysis of PICS will be conducted in patients with CCI and associated with long-term outcomes (survival and complete functional dependence) determined in Project #1. Specific Aim #3: to determine in a murine model of polymicrobial sepsis (cecal ligation and puncture) whether blockade of MDSC expansion prevents the development of PICS and supports protective immunity. To explore a causal relationship between MDSC expansion and the development of PICS, we will use two independent methods to block the expansion of MDSCs, and examine whether PICS develops, and protective immunity is either suppressed or maintained. The overall goal of Project #2 is to test the hypotheses that 1) sepsis drives the initial expansion of MDSCs, and 2) the chronic and continued expansion of the MDSC population is required for the PICS phenotype, and dismal long-term outcomes.